Cancer, which are a series of diseases characterized in abnormal cell proliferation and metastasis, has been one of the serious diseases that threaten the human health. According to the statistics from WTO, about 6 million peoples suffer newly from cancer every year all over the world. In China, cancer has been the second largest cause of death after cardio-cerebrovascular diseases.
At present, the common anti-tumor medicaments used in clinic are cytotoxic drugs, which have disadvantages such as poor selectivity, serious adverse reactions, and being easy to develop resistance. As the rapid development of techniques relating to biological genetic engineering and of research on molecular oncology and molecular pharmacology, it is gradually comprehended that the substantial mechanism of cells' cancerization involves the incoordinate cell signaling, i.e., the over-active signal transduction results in celluar immortalization as to most kinds of tumors. Therefore, molecules involved in the cell signaling are the important key to find novel anti-tumor medicaments, that is to say, the target sites of the key enzyme of the signal transduction pathway relating to tumor cell differentiation and proliferation can be used as the screening sites to find out a new anti-tumor medicament both exhibiting high performance, specificity and low toxicity and specifically combining with those target sites. At present, the said screening method has become a new way to investigate and develop anti-tumor medicaments.
PI3K-mTOR signal transduction pathway is one of the major protein tyrosine kinase signal transduction pathways. Phosphatidylinositol 3 kinase (PI3K) activates protein kinase B(PKB) by phosphorylation, and then the latter activates the mammalian target of rapamycin (mTOR) by phosphorylation. mTOR directly or indirectly participates in a plurality of regulations relating to cell proliferation and growth, and therefore is considered as a central regulator of cell proliferation. Many findings of research show that PI3K-mTOR signal transduction pathway is abnormally expressed in tumor cells, and plays an important role in the generation and development of a tumor. Therefore, PI3K-mTOR signal transduction pathway has become a promising target sites as to tumor therapy, because it is possible to specifically inhibit the growth of tumor cells if the said pathway is blocked, especially the activity of mTOR is inhibited.
Rapamycin, also called sirolimus, is a triene macrolide antibiotic first obtained through fermentation from the bacterium Streptomyces hygroscopicus isolated on the island of Rapa Nui by Wyeth Ayerst lab in 1975. It has antibacterial activities, and has been applied in clinic as a potent immunodepressant. Recent researches have shown that rapamycin exhibits significant antineoplasmic activities as a specific inhibitor for mTOR. In vitro, the growth of rhabdomyosarcoma cells can be significantly inhibited by only 1 ng/ml of rapamycin. Results obtained from many labs all over the world have also verified that rapamycin is a very good candidate for anti-tumor therapy. Rapamycin exhibits strong inhibitory effects on many tumors, such as rhabdomyosarcoma, neuroblastoma, spongioblastoma, medulloblastoma and small cell lung cancer, etc., and it has been clearly verified that its inhibitory effects on the growth of tumor cells are due to the combination with mTOR. Although rapamycin has exhibited fairly well anti-tumor activities before clinical application, its low water-solubility and chemical stability due to the macrolide structure thereof restrict its clinical development.
Recently, various rapalogs for mTOR-target therapy of tumor have been developed by many pharmaceutical companies. Among them, the representatives are CCI-779 (TemRapamycin) from Wyeth Co., RAD-001 (Everolimus) from Novarti Co. and AP23576 from Ariad Co. These rapalogs show similar anti-tumor effects as those of rapamycin and improved pharmacological properties without apparent adverse reactions. CCI-779 is suitable for intravenous injection and has been applied for the clinical therapy of patients suffered from advanced renal cancer. RAD-001 is suitable for oral administration and has been used in clinical tests at α stage for the treatment of small cell lung cancer. AP23576 has been used in clinical tests at β stage for the treatment of hematological cancers or solid tumors, showing a good prospect of being used as a drug. Therefore, it is desired to find an anti-tumor medicament with a superior activity, low toxicity and high specificity by structural modification using rapamycin as the mother core, which is much valuable in application.